In Vivo Administration of Interleukin 15 (IL-15) Safely Promotes the Survival and Proliferation of Adoptively Transferred Antigen-Specific T Cell Clones

The adoptive transfer of antigen-specific CD8⁺ cytotoxic T lymphocytes (CTL) that have been expanded in vitro is a promising treatment for human malignancies and infections. Interleukin (IL)-2 is frequently administered to support the in vivo survival of transferred T cells, but causes systemic toxicity when given in high doses and promotes the expansion of CD4⁺ regulatory T cells, which can inhibit antitumor immunity. IL-15, like IL-2, belongs to the four α-helix bundle family of cytokines and shares functional activities with IL-2, including binding to the IL-2 receptor (R) β and γ_c signaling components and promoting the proliferation of activated T cells in vitro. Despite the similar structure and in vitro function of IL-2 and IL-15, mice deficient in IL-15 or IL-15Rα have a marked reduction in natural killer (NK) cells, NKT cells, and CD8⁺ memory cells, whereas mice deficient in IL-2 or IL-2Rα have lymphoid hyperplasia and autoimmunity. Because of its critical role in the maintenance of T cell memory, IL-15 is an attractive alternative to IL-2 for augmenting adoptively transferred T cell immunity in humans. We administered IL-15 subcutaneously to nonhuman primates and evaluated toxicity, immunological effects, and peak and trough plasma levels. After establishing a safe regimen of IL-15 dosing, we evaluated the ability of IL-15 to support the survival of adoptively transferred CD8⁺ effector T cell (T_E) clones in vivo.

Results: IL-15 was administered subcutaneously to five macaques at doses ranging from 2.5 – 15 μg/kg, given either daily or every 3 days, respectively. The animals were monitored for clinical toxicity and plasma levels. Peripheral blood T cell subsets were enumerated at intervals and evaluated for phenotype and expression of Ki-67, a nuclear antigen expressed by cells undergoing proliferation. Daily administration of high-dose IL-15 resulted in a pronounced increase in the absolute numbers and Ki-67-expression of CD8⁺ T cells and NK cells, respectively, and preferentially expanded CD8⁺CD95⁺CCR7⁻ effector memory (T_EM) and CD8⁺CD95⁺CCR7⁺ central memory T cells (T_CM). However, daily IL-15 in doses of 5 – 15 μg/kg was associated with accumulation of IL-15 in serum, and caused toxicities that were reversible when IL-15 was discontinued. By contrast, intermittent IL-15 treatment every 3 days was safe and induced only a moderate increase in NK cells, CD8⁺ T_EM and T_CM, and enhanced expression of Ki-67 in these cell subsets. This coincided with an increase of the absolute number of cytomegalovirus (CMV)-specific CD8⁺ T cells in the peripheral blood, but total numbers of CD4⁺ FoxP3⁺ T cells were not increased with IL-15. We then examined the ability of IL-15 administered every 3 – 4 days for 3 weeks to support the in vivo persistence of T_CM-derived CMV-specific CD8⁺ T_E clones that were marked to express a truncated macaque CD19 surface molecule and transferred to the animals without prior lymphodepletion. As previously reported, CD8⁺ T_E clones derived from T_CM precursors survive in vitro in low-doses of IL-15 in the absence of T cell receptor stimulation, persist long term in vivo after transfer and revert to the memory pool (